The role of mortalin/GRP75 in neurodegeneration

Besides other disease-associated proteins, DJ-1 recently came into focus of neurodegenerative research, which was initially identified in autosomal recessive inherited forms of Parkinson’s disease (PD).

For a better understanding of the physiological functions of DJ-1 and the identification of associated signaling pathways, we screened for proteins interacting with DJ-1. Besides others, the mitochondrial stress protein mortalin was identified as new interaction partner. Interestingly, this interaction could confer to the already known protective function of DJ-1 at the mitochondria.

Mortalin is a nuclear encoded mitochondrial protein, which plays an important role in the stress response of the cell and is crucial for mitochondrial homeostasis. Localized in the mitochondrial matrix, mortalin acts as an essential component for the mitochondrial import of other matrix proteins and is responsible for their final conformation. It is already known, that mortalin is modulating aging processes and cells devoid of mortalin are not viable. Furthermore, overexpression of protein in cell culture or C. elegans extends lifespan. An important connection of mortalin to PD pathogenesis was established by the finding of decreased protein levels in affected brain regions of patients. These facts in terms of aging processes and neurodegeneration brought mortalin into focus of our research.

Thus, we performed a mutation screening of the mortalin gene in more than 1200 PD German patients and identified a novel disease-related variant. In parallel, a Spanish group found two additional novel mutations of this gene in PD patients. Consequently, the purpose of our project was the characterization of these three mortalin mutations, their impact on mitochondrial homeostasis and influence on adjacent signaling pathways.

Our results from neuronal dopaminergic cells showed that increased levels of physiological (wildtype) mortalin have a positive effect onto essential mitochondrial functions. Although mutated mortalin protein was imported as efficiently as the wildtype mortalin into the matrix of the mitochondria, the cytoprotective effect was abolished. Knockdown experiments showed that a reduction of physiological mortalin in neuronal dopaminergic cells lead to severe impaired functions of the mitochondria. This was demonstrated by a reduced mitochondrial membrane potential and increased production of reactive oxygen species. Complementation of the knockdown background with wildtype mortalin lead to a complete rescue of these defects. This was not observed for any of the three mutated forms of mortalin. In addition, skin fibroblasts from a carrier of the identified German mortalin variant showed an altered mitochondrial morphology.

In summary, our results reveal a loss of protective function of physiological mortalin due to these three novel disease-associated mortalin variants. This underscores the role of this important mitochondrial stress protein in the investigation of cell death during aging processes and strongly implicates molecular mechanisms of neurodegeneration in  PD.

Project: Lena Burbulla

Publication:

Burbulla LF, Schelling C, Kato H, Rapaport D, Woitalla D, Schiesling C, Schulte C, Sharma M, Illig T, Bauer P, Jung S, Nordheim A, Schöls L, Riess O, Krüger R (2010) Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis. Hum Mol Genet. 2010 Sep 16;